Sedgwick B
Imperial Cancer Research Fund, Clare Hall Laboratories, Potters Bar, Hertfordshire, England.
Cancer Res. 1992 Jul 1;52(13):3693-7.
The methylhydrazines, monomethylhydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine, are known carcinogens but only weak mutagens in the Ames test. Chemical oxidation of these compounds by potassium ferricyanide greatly enhanced their mutagenicity to an Escherichia coli ada mutant and converted them into inducers of the adaptive response of E. coli to alkylation damage. Enzymatic oxidation of monomethylhydrazine by horseradish peroxidase-H2O2 also yielded products which induced the adaptive response. Thus, methylhydrazines can be oxidized to active DNA-methylating derivatives which generate methylphosphotriesters (the inducing signal of the adaptive response), O6-methylguanine and/or O4-methylthymine (the miscoding bases repaired by the Ada protein) in DNA. These observations support the suggestion that metabolic oxidation of methylhydrazines in mammalian systems may be required to generate the mutagenic/carcinogenic derivatives.
甲基肼、一甲基肼、1,1 - 二甲基肼和1,2 - 二甲基肼是已知的致癌物，但在艾姆斯试验中只是弱诱变剂。这些化合物经铁氰化钾化学氧化后，其对大肠杆菌ada突变体的诱变性大大增强，并将它们转化为大肠杆菌对烷基化损伤适应性反应的诱导剂。辣根过氧化物酶 - H2O2对一甲基肼的酶促氧化也产生了诱导适应性反应的产物。因此，甲基肼可被氧化为活性DNA甲基化衍生物，这些衍生物在DNA中产生甲基磷酸三酯（适应性反应的诱导信号）、O6 - 甲基鸟嘌呤和/或O4 - 甲基胸腺嘧啶（由Ada蛋白修复的错配碱基）。这些观察结果支持了这样一种观点，即在哺乳动物系统中可能需要甲基肼的代谢氧化来产生诱变/致癌衍生物。
